Method of treatment of cardiac bradyarrhythmias

ABSTRACT

A method is disclosed for the treatment of cardiac bradyarrhythmias, i.e., slow, maladjusted heart rhythms and frequencies which often occur in heart block. It comprises intravenously administering therapeutic amounts of scopolamine methylbromide in order to increase the heartbeat frequency without causing certain undesirable side effects.

United States Patent [191 Goldberg 1 Oct. 9, 1973 [54] r gggf ggggfir 0FCARDIAC OTHER PUBLICATIONS Merck Index, 8th Edition, 1968, page 679.[75] Inventor: Leon 1. Goldberg, Atlanta, Ga

[73] Assignee: Arnar-Stone Laboratories, Inc., Mt. Primary ExaminerAlbe"Meyers Prospect, lll. Assistant ExaminerDaren M. StephensAttorney-Dawson, Tilton, Fallon & Lungmus [22] Filed: Sept. 27, 1972App]. No.: 292,665

[ 5 7] ABSTRACT A method is disclosed for the treatment of cardiacbradyarrhythmias, i.e., slow, maladjusted heart rhythms and frequencieswhich often occur in heart block. It comprises intravenouslyadministering therapeutic amounts of scopolamine methylbromide in orderto increase the heartbeat frequency without causing certain undesirableside effects.

6 Claims, No Drawings METHOD OF TREATMENT OF CARDHAC BRADYARRHYTHMIASBACKGROUND In the treatment of vagal-induced bradyarrhythmias as well asother malfunctions of the heart wherein heartbeat frequency slows, it isgenerally necessary that such frequency be increased. In the past, drugssuch as atropine and atropine sulfate have been used for that purpose.While such compounds are usually effective in increasing heartbeatfrequency, they often cause serious side effects which detract fromtheir usefulness. A particularly undesirable consequency of the use ofthese drugs is the possibility that the patient might sufferhallucinations and become agitated or even delirious. It will beappreciated that such central nervous system (CNS) side might beextremely hazardous for a cardiac patient who normally requires completerest and quiet.

Additionally, it has also been reported that atropine and likesubstances produce in some patients an initial arrhythmic bradycardiabefore the normal heartbeat frequency increase effects become apparent;this is also thought to be due to the central nervous system action ofsuch drugs. Other complications that can arise through theadministrction of these drugs are supraventricular and ventricularectopic beats or ventricular fibrillation.

SUMMARY The present invention is directed to overcoming the difficultiesinherent in the administration of drugs heretofore used in the treatmentof caridac bradyarr- .under bloodstream conditions. Scopolaminemethylbromide is of the formula:

0 CHzOH Specific homologs and analogs of scopolamine methylbromidebelieved to operate in a similar medicinal fashion would includescopolamine ethyl-, propyland butyl halides of bromine, chlorine andflourine and the structural isomers thereof.

In cardiac treatments of the type relevant to this invention it is oftendifficult or impossible to determine beforehand the optimum level ofheartbeat frequency that should be reached for a particular patient.Further, it is well-known that a beneficial heartbeat frequency for agiven patient under certain conditions may not be at all suitable foranother patient of differing condition. Therefore, in general it canonly'be said that the present invention should be utilized in order toraise the heartbeat frequency to a therapeutic level for a particularpatient. In normal situations, however, this rate has proved to be inthe range of from 70 to 110 heartbeats per minute, and the presentlydisclosed methods operate to raise the frequency to those levelswithoutundesirable CNS complications.

The total dosage required for such action will likewise vary frompatient to patient. The age, general size and cardiac condition of thesubject may influence this 'amount, although it is believed the patientsbody weight is the most important single factor. On that basis, thetotal dosage should fall within the range of about 0.75 to 10 microgramsper kilogram of body weight, the preferred dosage being about 5.7 mg/kg.

The invention may be advantageously practiced by a method of sequentialadministration. It is contemplated in this refinement that the drug(preferably scopolamine methylbromide) be given in a stepwise fashion byadministering minor fractional amounts of a total therapeutic dosage,with time intervals between each fraction and with continuous monitoringof the heart signs of the patient. The total dosage administered to thepatient is thereby carefully controlled to produce only the desiredstimulation of heartbeat frequency.

Scopolamine methylbromide has been utilized for many years as anantispasmodic or anticolanergic in the treatment of peptic ulcers andother gastro-intestinal disorders and for hyper hydrosis and excessivesalivation. Other uses have been found for this compound in connectionwith the treatment of functional diarrhea associated with hyper motiledysfunction of the intestinal tract. For such uses, the drug has usuallybeen administered subcutaneously or intramuscularly at intervals of 6 to8 hours. As reported in literature [See The Pharmacological Basis vofTherapeutics, 2d. Edition (1955), p. 559-560, and the US. Pat. ofVisscher (2,753,288)] the administration of the drug for such purposeshas not been found to increase or appreciably affect pulse rate.

DETAILED DESCRIPTION AND PREFERRED EMBQQIMENI The scopolaminemethylbromide to be administered in accordance with the presentinvention is commercially available in sterile aqueous solution,normally a 1 percent solution although other concentrations may beprepared and used, and is also available as a crystalline solid fromwhich aqueous solutions of desired concentration may be prepared. Thedrug may be produced by reacting scopolamine hydrobromide trihydratewith methyl bromide according to procedures.

fully explained in the aforementioned Visscher Patent.

As already explained, in the normal treatment of cardiac patientssuffering from bradyarrhythmias it has been found that no single doseregimen is applicable to all patients, and that individualexperimentation is usually required. In general, however, it has beenfound that a total intravenous dosage of from 0.75 to 10.0 microgramsper kilogram of patient body weight, and preferably not exceeding 6.0micrograms per kilogram of body weight, will serve the therapeuticpurposes outlined above.

The importance of carefully regulating dosage levels is apparent fromthe further discovery that an insufficient dose might produce a shortperiod of increased vagal activity (i.e., the heart rate might slowfurther) whereas if the dose is too large the heart rate might increaseexcessively. It is therefore particularly advantageous to sequentiallyadminister the drug in fractional amounts of the total dosage whilecontinually monitoring the heartbeat frequency of the patient. in such away, the administration can be terminated when the heartbeat reaches thedesired frequency, e.g., a level of from 70 to 110 heartbeats perminute.

In further clinical tests, it has been found that the correct dosagelevel can most effectively be reached by an electrocardiagraphicallymonitored sequential administration of scopolomine methyl bromide over atotal time period of to 30 minutes according to the following schedule:

a. initially intravenously administering an amount of the drug of fromone-eighth to one-fourth of the total dosage;

b. then, after a period of from 2 to 10 minutes, intravenouslyadministering an amount of from one-eighth to one-fourth of the totaldosage;

c. then, after a period of from 2 to 10 minutes, intravenouslyadministering from one-eighth to one-fourth of the total dosage;

d. finally, after a period of from 2 to 10 minutes intravenouslyadministering the remaining fraction of the total dosage.

Once the optimum total dosage for a given patient has been determined, alesser number of steps, or even In the course of these clinical tests,the patients heartbeat was initially checked, and a minor fractionalamount of an anticipated total dosage was given intravenously. Afterfive minutes this was repeated, and the process continued with fiveminute periods between doses. The total dose was anticipated to be 5.7micrograms scopolamine methylbromide per kilogram body weight, and wasadministered according to the following schedule, with continuousmonitoring:

a. is close initially;

b. 5!; dose 5 minutes later;

c. A dose 5 minutes later; and

d. k dose 5 minutes later.

TABLE Final Initial Initial Heartbeat Second Heartbeat Third HeartbeatFourth heartbeat Total heartbeat, dose, frequency, dose, frequency,dose, frequency, dose, frequency, dosage, Age of patient beat/min. g.beat/min. pg. beat/min. g. beat/min, pg. beat/min. g.

72 58 82 58 103 116 124 232 51 46 56 46 62 Q2 82 368 67 41 41 82 97 32870 52 90 52 104 208 103 52 113 52 129 105 134 332 82 57 98 57 124 114138 228 82 48 82 48 92 96 113 384 75 4.2 71 -12 98 84 127 168 86 70 0O70 113 140 158 280 87 42 113 -12 144 85 155 339 54 75 6'2 75 72 110 50082 66 03 66 123 132 134 468 82 52 66 52 103 105 329 16 55 82 55 100 110120 220 82 7 80 47 98 94 128 188 66 61 75 61 75 123 120 245 Q0 46 90 4690 92 127 378 90 80 97 80 97 116 340 86 80 83 80 83 160 143 540 90 48 9718 97 96 105 384 a single-step administration of the drug, may beappropriate or desirable for subsequent treatment.

In the following example and accompanying clinical data, it has beenfound that scopolamine methylbromide, when employed according to theprocedures herein, produces the desired effect of increasing heartbeatfrequency in patients with cardiac brad'yarrhythmias. In no such caseshave hallucinations and other undesirable CNS side effects of the typeassociated with atropine and allied substances been observed orreported. Such favorable results are believed to arise at least in partfrom the fact that scopolamine methylbromide is a quaternary ammoniumcompound which does not cross the blood-brain barrier to produceundesirable effects upon the central nervous system.

The following example serves to illustrate further the nature of thepresent invention and the manner by which it can be practiced.

H HG C CH2 /Br I t CHzOH o CH3N nc-o-b- OH: I

I HO 0 CH2 in a total dosage sufficient to raise the heartbeat frequencyto a therapeutic level.

2. The method of claim 1 wherein said dosage is sequentiallyadministered in fractional amounts of said total dosage whilecontinuously monitoring the heartbeat frequency, said administrationbeing terminated when said heartbeat frequency reaches a therapeuticlevel.

3. The method of claim 1 wherein said therapeutic heartbeat frequency isfrom 70 to 110 heartbeats per minute.

4. The method of claim 1 wherein said total dosage is from 0.75 to 10.0micrograms of scopolamine methylbromide per kilogram of patient bodyweight.

5. The method of claim 4 wherein said total dosage is sequentiallyadministered as needed until the heartbeat frequency reaches a level offrom 70 to 1 l0 heart beats per minute, according to the followingschedule, while continuously monitoring said heartbeat frequency:

a. initially administering an amount of from oneeighth to one-fourth ofsaid total dosage;

b. after a period of from 2 to minutes, administering an amount of fromone-eighth to one-fourth of said total dosage;

c. after a period of from 2 to 10 minutes, administering an amount offrom one-eighth to one-fourth of said total dosage; and

d. after a period of from 2 to 10 minutes, administering the remainingfraction of said total dosage.

6. The method of claim 1 wherein said total dosage is about 5.7micrograms scopolamine methylbromide is sequentially administered asneeded until the heartbeat frequency reaches a level of from 70 to 1 l0heartbeats per minute, according to the following schedule, whilecontinuously monitoring said heartbeat frequency:

a. initially administering an amount equal to about one-eighth of saidtotal dosage;

b. after a period of about 5 minutes, administering an amount equal toabout one-eighth of said total dosage;

c. after a period of about 5 minutes, administering an amount equal toabout one-fourth of said total dosage; and

d. after a period of about 5 minutes, administering the remainingfraction of said total dosage.

2. The method of claim 1 wherein said dosage is sequentiallyadministered in fractional amounts of said total dosage whilecontinuously monitoring the heartbeat frequency, said administrationbeing terminated when said heartbeat frequency reaches a therapeuticlevel.
 3. The method of claim 1 wherein said therapeutic heartbeatfrequency is from 70 to 110 heartbeats per minute.
 4. The method ofclaim 1 wherein said total dosage is from 0.75 to 10.0 micrograms ofscopolamine methylbromide per kilogram of patient body weight.
 5. Themethod of claim 4 wherein said total dosage is sequentially administeredas needed until the heartbeat frequency reaches a level of from 70 to110 heartbeats per minute, according to the Following schedule, whilecontinuously monitoring said heartbeat frequency: a. initiallyadministering an amount of from one-eighth to one-fourth of said totaldosage; b. after a period of from 2 to 10 minutes, administering anamount of from one-eighth to one-fourth of said total dosage; c. after aperiod of from 2 to 10 minutes, administering an amount of fromone-eighth to one-fourth of said total dosage; and d. after a period offrom 2 to 10 minutes, administering the remaining fraction of said totaldosage.
 6. The method of claim 1 wherein said total dosage is about 5.7micrograms scopolamine methylbromide is sequentially administered asneeded until the heartbeat frequency reaches a level of from 70 to 110heartbeats per minute, according to the following schedule, whilecontinuously monitoring said heartbeat frequency: a. initiallyadministering an amount equal to about one-eighth of said total dosage;b. after a period of about 5 minutes, administering an amount equal toabout one-eighth of said total dosage; c. after a period of about 5minutes, administering an amount equal to about one-fourth of said totaldosage; and d. after a period of about 5 minutes, administering theremaining fraction of said total dosage.